Project 2 Summary Functional Consequences of Putative Pharmacotherapies for Cocaine Dependence in Animal Models of Cocaine Exposure Drs. Sara Jones/Linda Porrino, co-PI's; Drs. Sam Deadwyler and Mark Ferris, co-I's Cocaine abuse is a significant public health problem, but attempts to develop effective treatments for cocaine abuse and dependence have met with only limited success. One promising development in the clinic has been the use of combination medications to treat the broad range of symptoms and neuroadaptations that result from cocaine exposure. In the prior funding period, the Center found that stimulant drugs, specifically amphetamines, were among the more efficacious strategies for reducing cocaine reinforcement. Building on this foundation, new preliminary data, and advice from the Center's clinical partners we have chosen to examine the stimulant releaser phenmetrazine and its oral pro-drug, phendimetrazine, which have much lower abuse liability to address the dysregulation of dopamine function that is characteristic of cocaine abuse. Another hallmark characteristic of cocaine dependence is reduced prefrontal cortical function and accompanying deficits in behavioral control and cognition. Because multiple transmitter systems are involved in regulating prefrontal cortical function and glutamatergic output from this region, drugs that act on specific prefrontal circuits have been selected for testing as combination drug candidates with phenmetrazine. These drug combinations will be chosen in consultation with other Center Projects and our clinical partners. In the previous funding cycle, we established neurobiological ?signatures? of functional activity, dopamine dynamics, cognitive function and cortical processing that relate to cocaine self-administration and its pharmacological manipulation. This Project will use these data to form the foundation of studies proposed here to examine the neurobiological consequences of chronic phenmetrazine and combination drug therapies in rodent and nonhuman primate models of cocaine use and abuse. Specific Aim 1 will use rats to measure changes in the function of the dopamine system and identify brain regions with altered metabolic activity after cocaine self- administration and chronic treatment with combinations of candidate medications. Specific Aim 2A will use nonhuman primates to characterize the effects of cocaine cues on PET measures of cerebral metabolism after chronic cocaine exposure and treatment with combination medications. Specific Aim 2B will evaluate the effects of chronic cocaine exposure with combination medications on cerebral metabolism during the performance of a cognitive task. In addition, electrophysiological recordings of prefrontal cortex will be used to evaluate changes in neural circuitry induced by combination medications that alleviate cocaine addiction.